P650: A FIRST-IN-HUMAN PHASE 1 TRIAL OF NX-5948, AN ORAL BTK DEGRADER, IN PATIENTS WITH RELAPSED AND REFRACTORY B-CELL MALIGNANCIES
Authors: K. Linton, G. P. Collins, D. El-Sharkawi, R. Mous, F. Forconi, M. Tan, S. Nandakumar, E. Meredith, K. L. Jameson, S. G. Injac, J. Doorduijn
Journal: HemaSphere (2022)

Background: Bruton's tyrosine kinase (BTK) is a key component of the B-cell receptor (BCR) signaling pathway and chronic activation of BTK-mediated BCR signaling is a hallmark of many B-cell malignancies. BTK-targeted therapy has been shown to be safe and effective in a variety of B-cell lymphomas, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and Waldenström macroglobulinemia (WM). However, BTK inhibitor (BTKi) resistant disease remains a clinical challenge with limited options for salvage therapy and overall poor patient outcomes. BTK degradation may be effective in patients who have developed resistance to BTKi or in B-cell indications where treatment with BTKi has been less effective. NX-5948 is an oral, small molecule that induces BTK degradation through the recruitment of cereblon, an adaptor protein of the E3 ubiquitin ligase complex, and does not induce degradation of other cereblon neosubstrates. NX-5948 degrades both wild type BTK and BTKi resistant mutants (C481) and inhibits ibrutinib-resistant tumor cell line growth at concentrations where ibrutinib and acalabrutinib are inactive. NX-5948 potently inhibits tumor growth in xenograft models that contain either wild type BTK or BTKi-resistant mutations. Further, NX-5948 crosses the blood-brain barrier, thus positioning it as a therapeutic agent in patients with primary central nervous system lymphoma (PCNSL) and other lymphomas that have CNS involvement. Aims: The primary objectives are to evaluate safety and tolerability, determine the maximum tolerated dose (MTD; Phase 1a only), and the early clinical activity in each expansion cohort (Phase 1b only) of NX-5948 in patients with relapsed and refractory B-cell malignancies. Methods: NX-5948-301 is a first-in-human, dose escalation (Phase 1a) and cohort expansion (Phase 1b) study designed to evaluate the safety, tolerability, and preliminary efficacy of NX-5948 in adult patients with relapsed and refractory B-cell malignancies. NX-5948 will be given orally daily and dose escalation will proceed using a standard 3 + 3 design. There will be up to 5 expansion cohorts in Phase 1b composed of patients with the following tumor types: (a) CLL/SLL with a C481 mutation; (b) CLL/SLL without a C481 mutation; (c) aggressive subtypes diffuse large B-cell lymphoma (DLBCL) and MCL; (d) indolent subtypes FL, MZL, and WM; and (e) primary/secondary CNS lymphoma. Other key eligibility criteria include 2 or more prior lines of therapy (only 1 prior for WM and PCNSL); measurable disease; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Up to 130 patients (30 in Phase 1a, 100 in Phase 1b) will be enrolled and treated until disease progression or unacceptable toxicity. Results: Enrollment in this study has begun in Europe. Summary/Conclusion: Accrual is ongoing. Clinical trial information: NCT05131022.